A review on lawsone-based benzo[a]phenazin-5-ol: synthetic approaches and reactions

Phenazine systems are an important class of aza-polycyclic compounds that are easily found in nature and isolated as secondary metabolites primarily from Pseudomonas, Streptomyces, and a few other genera from soil or marine habitats. Moreover, various synthetic phenazine analogs are known for their pharmaceutical activities. Among various phenazines, benzo[a]phenazines are structural subunits in a variety of important natural products and have been given special attention due to their unique biological properties in various fields. In this review article, we highlight the synthesis of benzo[a]phenazin-5-ol derivatives from lawsone and benzene-1,2-diamines and their applications for the construction of a variety of five and six membered fused heterocycles such as pyranophenazines, spiropyranophenazines, pyridophenazines, furophenazines, benzochromenophenazines and oxazinophenazines during the period of 1995 to 2021.


Introduction
Phenazine systems are an important class of aza-polycyclic compounds that are easily found in nature. More than 6000 phenazine-containing compounds have been recognized and reported during the past century, including natural phenazines and compounds synthesized based on the phenazine skeleton. Phenazine natural products are isolated as secondary metabolites primarily from Pseudomonas, Streptomyces, and a few other genera from soil or marine habitats. The biological properties of this class of natural products have been reviewed. In 1986, Turner and Messenger described the natural occurrence and some properties of phenazines, biosynthesis, secondary metabolism and the physiological signicance of phenazine production in a review article. 1 Aer that, the role of phenazine pigments as antibiotics and virulence factors was reviewed by Kerr in 2000. 2 Next, Laursen and Nielsen described exclusively with a representative selection of biologically signicant phenazines, their natural occurrence, their biosynthesis, the design and synthesis of analogues, and their biological function and possible mode of action in 2004. 3 The progress in the isolation of new phenazine natural products, new insights in their biological function, and particularly the now almost completely understood biosynthesis has been briey reviewed recently. 4 Moreover, various synthetic phenazine analogs are known for their pharmaceutical activities such as antifungal, antimalarial, antileishmanial, antihepatitis C viral replication, trypanocidal, inhibition of the cyclooxygenase, interactions of serum albumins, antimicrobial, anti-inammatory, antitumor, as well as insecticidal activity. [5][6][7][8][9][10][11][12][13][14][15][16] Fluorescent phenazine derivatives both natural and synthetic, are also of interest because of their rapidly expanding applications as emitters for electroluminescence devices, 17 organic semiconductors, 18 photo-sensitizers in photodynamic therapy, 19 promoter for proliferation, 20 dyesensitized solar cells (DSSCs), 21 electrochemical, and biosensors sensitive to H 2 O 2 , glucose, and lactose. [22][23][24] The synthetic routes for the synthesis of this scaffold have been reviewed. The general approaches for synthesis of phenazines include the Wohl-Aue method, Beirut method, condensation of 1,2-diaminobenzenes with 2C-units, reductive cyclization of diphenylamines, oxidative cyclization of 1,2-diaminobenzene/ diphenylamines, Pd-catalyzed N-arylation, multicomponent approaches and benzyne intermediate has been reviewed by Chaudhary and Khurana in 2018. 25 Recently, Elhady and coworkers reviewed the synthesis of phenazines, either chemically or biologically and, also the different reactions of them and some of their biological importance, and their applications in the development of electrochemical sensors, biosensors and dye-sensitized solar cells (DSSCs). 26 Among various phenazine derivatives, benzo[a]phenazines that have a napthoquinone and phenazin backbone in their structures are structural subunits in a variety of important natural products and has been given special attention due to their unique biological properties in various elds such as dual inhibitors of topoisomerase I and II and are useful as antitumor agents. 27 2-Hydroxy-1,4-naphthoquinone, or lawsone, or hennotannic acid, is one of the simplest naturally occurring naphthoquinones which can be obtained from the extract of dried powdered leaves of henna. Lawsone as a red-orange pigment is traditionally used for coloring hair and dying nails and skin, silk, wool and leather. It is reveals a long list of applications, including skin protection from ultraviolet radiation, corrosion inhibition for steel, antiaging additive to vulcanized natural rubber, oxidation of chlorinated compounds and sensitive colorimetric and electrochemical sensor for anions. Moreover, it has been used as the starting material for the synthesis of a variety of biologically active compounds and materials with interesting properties. [28][29][30][31] This review highlights the synthesis of benzo[a]phenazin-5-ol derivatives from lawsone and benzene-1,2-diamines and their applications for the construction of a variety of ve and six membered fused heterocycles.

Synthesis of benzo[a]phenazin-5ols
The rst synthesis of 5,7-dihydrobenzo[a]phenazin-5-one derivatives 1 in good yields (62-94%) was reported by Rehberg and Rutherford in 1995. The general synthesis involved condensation of aromatic 1,2-diamines 2 with 2-hydroxy-1,4naphthoquinone (lawsone) (3) in the presence of acetic acid under reux conditions for overnight (Scheme 1). 32 In 2002, Kaupp and Naimi-Jamal reported synthesis of benzo [a]phenazin-5-ol (4) in 100% yield by the one-pot condensation reaction of 3 and o-phenylenediamine (2a) in solid-state 1 : 1 runs in 15 min at 70 C. If the same reaction was performed as a melt at 120 C for 30 min, a 100% yield was also obtained (Scheme 2). 33 In 2013, Jain and co-workers described synthesis of tetracyclic phenazine derivatives 4 and 5 in 38-97% yields. The reaction of 3 with 2a in reuxing EtOH in the presence of AcOH as catalyst for 4 h afforded 4 while reuxing with 2,3-diaminotoluene (2e) gave the mixture of the regioisomers 5a-b. These reactions were also carried out under mortar-pestle grinding technique, where the reaction was complete in lesser time and in enhanced yield (Scheme 3). 34 In 2014, Sekar and co-workers developed synthesis of benzophenazines 4 and 6a-c in 96-98% yields from lawsone (3) and 1,2-benzenediamines 2 under ultrasound irradiation in an aqueous media at 27 C for 20-24 min. Also, the reaction of 3 and 2a was carried out by conventional method by reuxing in glacial acetic-acid for 2 h afforded the desired product 4 in 89% yield (Scheme 4). 35

Synthesis of benzopyranophenazines
In 2011, Jiang and co-workers synthesized highly functionalized benzo[a]pyrano[2,3-c]phenazine derivatives 7 in 81-92% yields via one-pot two-step reactions of 3, diamines, aldehydes and malononitrile in AcOH under microwave irradiation at 120 C for 7-14 min. The formation of 7 is expected to proceed via initial condensation of 3 and diamine to afford benzo[a] phenazin-5-ol derivatives 4, 6a and 6d, which undergoes in situ Michael addition with 2-benzylidenemalononitrile 8, formed from condensation of aldehydes with malononitrile, to yield intermediate 9, which is then cyclized to afford the product 7 (Scheme 5). 36 Next, an efficient one-pot two step quantitative procedure for the preparation of functionalized benzo[a]pyrano [2,3-c]phenazine derivatives 10 was reported from four-component reaction of 3, 2a, aromatic aldehydes, and malononitrile in the presence of nano CuO (10 mol%) as the catalyst at 75 C under solventfree conditions. The mechanism for the formation of the products has been suggested in Scheme 6. First, 3 tautomerizes to intermediate 11. The initial condensation of 11 with 2a affords 6H-benzo[a]phenazin-5-one (12), which in tautomerism equilibrium causes to prepare 4. In addition, standard Knoevenagel condensation of malononitrile and aryl aldehydes in the presence of nano CuO as the catalyst afforded benzylidenemalononitrile (13). The Michael addition of 4 with 13 formed intermediate 14, which in subsequent cyclization and tautomerism gave the corresponding product 10. The wide ranges of substituted and structurally diverse aldehydes afforded the corresponding products in high to excellent yields (89-93%). 37 Aer that, an efficient one-pot two-step quantitative procedure for the preparation of functionalized benzo[a]pyrano [2,3-c] phenazine derivatives 15 in 87-94% yields reported from fourcomponent reaction of 3, 2a, aromatic aldehydes, and malononitrile in the presence of basic ionic liquids such as 1-butyl-3methylimidazolium hydroxide, 3-hydroxypropanaminium acetate, pyrrolidinium formate, pyrrolidinium acetate, 1,8diazabicyclo [5.4.0]-undec-7-en-8-ium acetate, and piperidinium formate as the catalysts under solvent-free conditions in 75 C for 6-10 min (Scheme 7). The mechanism of the reaction is similar to the proposed mechanism in Scheme 6. 38 Later, DABCO as an efficient and reusable solid base catalyst was used for the one-pot, two-step, four-component synthesis of benzo [ In 2016, a one-pot, two-step procedure was used to synthesize functionalized benzo[a]pyrano [2,3-c]phenazine derivatives 19 in 85-96% yields from a four-component condensation reaction of 3, 2a, aromatic aldehydes, and malononitrile in the presence of 1,3,7-trimethylpurine-2,6-dione (caffeine) as an expedient and reusable solid base catalyst under conventional heating and microwave irradiation. The mechanism for the formation of the products has been proposed in Scheme 9. On the basis of this mechanism, at rst, 3 tautomerizes to intermediate 11. The primary condensation of 11 with 2a obtains 12, which in tautomerism equilibrium reasons to prepare 4. On this mechanism, caffeine is an impressive catalyst to form the olen 20, which easily prepares in situ from Knoevenagel condensation of aldehyde with malononitrile. The Michael addition of 4 with 20 in the presence of caffeine nally give intermediate 21, which then causes the intermolecular ring to be formed aer a tautomeric proton shi to produce 19. 40 Next, Firouzabadi and his group described theophylline immobilized on superparamagnetic Fe 3  26a-b in 91-94% yields has been reported via the reaction between 3 (2 mmol), 2a (2 mmol), malononitrile (2 mmol) and terephtalaldehyde or isophtalaldehyde (1 mmol) in the presence of Fe 3 O 4 @SiO 2 -TCT-theophylline in EtOH under reux conditions for 30-40 min (Scheme 10). 41 Aer that, the nanostructured a-chitin/ZnO was used as reusable nanocatalyst in the green synthesis of benzo[a]pyrano(2,3-c)phenazine derivatives 27 in 80-95% yields through a four-component domino reaction of 3, o-phenylenediamines, aromatic aldehydes and malononitrile under microwave irradiation in EtOH at 78 C within 4-7 min. The mechanism is shown in Scheme 11. 6H-Benzo[a]phenazin-5-one (12) in tautomeric equilibrium with 4 was obtained aer the nucleophilic attack of 2a to 3 followed by dehydration. Subsequent Michael addition of 4 to benzylidenemalononitrile, produced via Knoevenagel condensation of arylaldehydes with malononitrile catalyzed by Ch/ZnO, provided the desired product 27 aer cyclization of intermediate 28. 42 In addition, hyperbranched polyglycerol functionalized graphene oxide (GO-HPG-SO 3 H) as an efficient reusable catalyst was employed in the synthesis of benzo[a]pyrano-[2,3-c]phenazine dyes 29 in 85-95% yields via one-pot reaction between 3,   Ultimately, a tautomeric proton shi produced the nal product 40. 46 Further, Singh et al. described a pragmatic and swi method for the synthesis of benzo[a]pyrano[2,3-c]phenazine derivatives 46 in 84-92% yields via one-pot, multi-component reaction of 3, benzene-1,2-diamines, aromatic aldehydes and malononitrile in the presence of supramolecular b-cyclodextrin as a biodegradable and reusable catalyst in EtOH : H 2 O (1 : 1) solvent at 70 C for 50-90 min. A plausible reaction mechanism is depicted in Scheme 16. The desired product is expected to form by the Knoevenagel condensation followed by Michael addition and at last cyclization within the cavity of b-CD where it is anticipated that seven free primary -OH groups of b-CD execute synergistically as a procient host and supramolecular catalyst. Initially, the condensation of 3 and diamine takes place to afford the intermediate 47 phenazin-5-ol. In the mean time, Ce ions also trigger the aromatic aldehyde to condense with malononitrile, an active methylene compound, to form the Knoevenagel adduct. Now, benzo[a]phenazin-5-ol, adds up to the Knoevenagel adduct, being an excellent activated Michael acceptor, following 1,4addition, intramolecular cycloacondensation affords the nal desired product 50. 48 Aer that, a green and rapid sonochemical research to preparation of the benzo[a]-pyrano[2,3-c]phenazines 51 in 85-  49 Further, Taheri and his group described the reaction of 3 with benzene-1,2-diamines, aldehydes and malononitrile in the presence of Cu-benzene dicarboxylic acid (Cu-BDC) under ultrasonic irradiation at 60 W power for 15-30 min afforded benzophenazine derivatives 56 in 83-97% yields. The proposed mechanism for the production of 56 is presented in Scheme 19. In the rst stage, the condensation of 3 and o-phenylenediamines leads to the production of benzo[a]phenazin-5-ol 57. Additionally, the Knoevenagel condensation aldehyde and malononitrile in the presence of Cu-BDC as acid catalyst produce intermediate 58. The Michael addition of 57 with 58 from Knoevenagel condensation leads to the production of 59 that occurs in the presence of acidic Cu-BDC and an intermediate 60 is produced. Finally, in the course of a cyclization followed by tautomerism, the nal product 56 produced and the catalyst returns to the reaction cycle. 50 In 2016, benzo[a]pyrano[2,3-c]phenazine derivatives 61 were synthesized in 90-95% yields via a one-pot, two-step procedure from a three-component condensation reaction of 3, 1,2diamines, and tetracyanoethylene in the presence of pyridine (20 mol%) as an efficient catalyst in EtOH at room temperature for 30-45 min. The mechanism for the formation of the products is proposed in Scheme 20. On the basis of this mechanism, at rst, 3 tautomerizes to intermediate 11. The primary condensation of 11 with 1,2-diamine gives compound 62, which in tautomerism equilibrium helps to prepare compound 63. Then, based on the nucleophilicity of pyridine, the nucleophilic addition of pyridine to the electron-decient tetracyanoethylene and subsequent protonation in the presence of compound 63 gives intermediate 64, followed by the attack of the anion on the cation part of intermediate 64 to form the product 61 via intramolecular cyclization and a tautomeric proton shi. 51 In 2012, one-pot two-step domino protocol for the efficient synthesis of uorescent benzo[a]-phenazine fused derivatives 65 in 82-92% yields was developed. The synthesis was achieved by reacting 3, ortho-phenylenediamines, aromatic aldehydes and cyclic 1,3-dicarbonyl compounds in the presence of a catalytic amount of p-TSA in PEG-400 at 70 C for 2-2.5 h. A speculative mechanistic explanation for this reaction is provided in Scheme 21. The formation of 65 proceeds via initial condensation of 3 and diamine to afford benzo[a]phenazin-5-ol derivatives 4 and 6a as reported which in situ generates an orthoquinone methide (o-QM) intermediate 66 upon nucleophilic addition to aldehyde. Subsequent Michael addition of the o-QM with a cyclic 1,3-dicarbonyl compound, followed by cyclization and dehydration leads to the formation of 65. 52 In 2015, Jeong and co-workers reported a synthetic route to produce tetrahydro-1H-benzo[a]-chromeno[2,3-c]phenazin-1ones 67 in 88-95% yields by the straightforward, efficient and convenient approach of a three-component reaction between aromatic aldehydes, 4 and active methylene compounds under neat conditions in the presence of an ionic liquid, tetramethyl guanidiniumchlorosulfonate (TMG IL), at 60 C for 45-65 min. The TMG IL was used as a solvent and as a catalyst under reusable conditions. The title compounds were screened for their in vitro antioxidant activity and it was found that most of the compounds are effective against reactive oxygen species.
The majority of them also have excellent in vitro anti-cancer activity on two human cancer cell lines, HeLa and SK-BR-3, compared with standard drugs. The TMG IL-catalyzed synthetic sequence of the title compounds is presented in Scheme 22, and may proceed via an ortho-quinone methide (o-QM) intermediate. At the beginning, nucleophilic addition of 4 to an aldehyde takes place and subsequently Michael addition of the o-QM to an enolic form of a cyclic 1,3-dicarbonyl, followed by the addition of the benzyl hydroxy moiety to the carbonyl of the ketone 68, provides a cyclic hemiketal 69, which on dehydration affords 67. 53 Next, an efficient and quantitative procedure for the synthesis of functionalized benzo[c]chromeno[2,3-a]phenazine derivatives 70 in 77-99% yields by one-pot, two-step fourcomponent condensation of 3, 2a, aromatic aldehydes, and cyclic 1,3-dicarbonyl compounds were developed using catalytic amounts of H 2 SO 4 and phosphotungstic acid in EtOH/H 2 O (1 : 1) under reux and also with Brønsted acidic ionic liquid [NMP]H 2 PO 4 , which acts as catalyst and medium at 80 C (Scheme 23). 54 In 2018, silica sulfuric acid (SiO 2 -SO 3 H) has been used as an effective and reusable solid catalyst for the one-pot, two-step,  57 In 2016, a sequential one-pot two-step four-component reaction for the efficient synthesis of 16-(aryl)benzo[a]indeno plays a key role as a Brønsted-Lowry acid catalyst in this reaction. The formation of 77 proceeds via initial condensation of 3 and 2a to afford 4 as reported, which in situ generates an orthoquinone methide (o-QM) intermediate 78 upon nucleophilic addition to aldehyde. Subsequent Michael addition of the o-QM with 1,3-indandione, followed by cyclization and dehydration, leads to the formation of product 77. 58 Aer that, a highly efficient one-pot, two-step microwaveassisted procedure was applied for the rapid and green synthesis of benzo[a]phenazine annulated heterocyclic ring systems 79 in 83-94% and 80 in 85-95% yields from the threeor four-component condensation reactions of 3, 2a, aromatic aldehydes and 1,3-indandione or 3 using L-proline as a bifunctional organocatalyst in water at 70 C for 10-20 min (Scheme 28). Moreover, the catalyst can be recovered and reused several times without much loss of its performance. Also, the reactions were examined with aliphatic aldehydes such as n-heptanal and n-octanal but the related products were not obtained in these reaction conditions even aer 20 min. The probable mechanism for the domino synthesis of 79 and 80 using L-proline is similar to the proposed mechanism in Scheme 28. conditions, using microwave irradiation (180 W, 75 C) for 7-10 min. A plausible mechanism is illustrated in Scheme 32. Based on this mechanism, at rst, 3 tautomerizes to intermediate 24. The primary condensation of 24 with diamine gives 6H-benzo[a]-phenazin-5-one 94, which in tautomerizes to benzo phenazin-5-ol 106. Simultaneously the Knoevenagel condensation between an aldehyde and Meldrum's acid yields the arylidene Meldrum's acid 107. Subsequently 106 undergoes Michael type addition to arylidene Meldrum's acid 107 to give intermediate 108 which undergoes cyclization with loss of acetone and carbon dioxide simultaneously to afford the desired compound 104. 66 Next, the pyrano-phenazine derivatives 109 were synthesized by an efficient procedure using the reaction between benzo[a] phenacin-5-ols with the condensation product of an aldehyde with Meldrum's acid in the presence of a catalytic amount of Et 3 N at ambient temperature. The rst step consists in the condensation reaction between diamines and 3 in AcOH as solvent for 24 h to afford benzo[a]phenazin-5-ols 110 in 76-91% yields. The latter were used as C-nucleophiles to react with the condensation product of aromatic aldehyde with electrondonating and electron-withdrawing functional groups with Meldrum's acid in MeCN/EtOH (3 : 1) in the presence of Et 3 N (10 mol%) for 24 h to furnish the desired product 109 in 68-92% yields (Scheme 36). 67 Further, Yazdani-Elah-Abadi and his co-workers reported an efficient and environmentally benign procedure for the  68 In 2019, Kucherenko and co-workers reported synthesis of enantioselectively tetrahydropyran-fused benzo[a]phenazins 120 in 85-95% yields from b,g-unsaturated a-keto esters and benzo[a]phenazin-5-ol (4) in the presence of bifunctional tertiary amine-squaramide catalyst in THF at room temperature for 4-6 h (Scheme 38). 69 A one pot three-component reaction for the synthesis of benzo   74 In 2017, a series of benzo[a]-phenazine derivatives 140 as hybrid molecules of phenazine, pyran, indole and 1,2,3-triazole pharmacophores were constructed in 55-82% yields. Firstly, the   76 Further, a series of pyrano-fused benzophenazines 146-147 in 75-92% yields were synthesized using a bifunctional thiourea-based organocatalyst from the one-pot, two-step fourcomponent reaction of 3, benzene-1,2-diamines, malononitrile or its derivatives and isatins or aromatic aldehydes in water under reux conditions for 2-7 h. The proposed mechanism is outlined in Scheme 46. They believe that the condensation reaction between 3 and the benzene-1,2-diamine leading to the corresponding benzo[a]phenazin-5-ol 148 does not need any catalyst. However, organocatalyst plays signicant role in other steps, and it activates both the electrophile and nucleophile through its thiourea moiety and basic amine moiety, respectively. The Knoevenagel condensation of isatin or aldehyde with malononitrile affords 149, which undergoes a Michael addition with 148 to form intermediate 150 in the presence of organocatalyst. A subsequent cyclization leads to the formation of 151 which undergoes tautomerization to form the corresponding nal products 146-147. 77 In  78 Later, a green strategy for the synthesis of a biologically and pharmaceutically interesting multi-functionalized diverse spiro-benzo[a]phenazine annulated heterocycles 156 in 76-91% yields by one-pot, two-step domino reaction starting from 3, benzene-1,2-diamines, a cyclic carbonyl compound, and 1,3indandione in the presence of a basic ionic liquid (1-butyl-3methylimidazolium hydroxide: [BMIM]OH) as a reusable catalyst with the assistance of microwave irradiation (300 W) under solvent-free conditions at 100 C for 8-12 min. The probable mechanism is given in Scheme 48. On the basis of this suggested mechanism, the primary condensation of 3 with benzene-1,2-diamines in the presence of [BMIM]OH gives benzo [a]phenazin-5-ols 157. Then, the Knoevenagel condensation between 157 and cyclic ketones produce adduct 158, which act as a Michael acceptor. The 1,3-indandione attacks the Knoevenagel adduct 158 in a Michael-type addition to produce the intermediate 159, which then makes the inner molecular ring to be formed aer a tautomeric proton shi to generate 156. 79 Aer that, for synthesis of 3-amino- increased the electrophilicity of reactants, which simplies the reaction. Moreover, in the presence of monosubstituted benzene-1,2-diamine, major and minor isomers of the corresponding products are generated. 80 Next, Kumar et al. described a domino protocol for the synthesis of structurally diverse spiroannulated pyrimidophenazines 161 in 89-96% yields involving a fourcomponent reaction of 3, 2a, cyclic ketones and amino derivatives in the presence of erbium doped.
TiO 2 nanoparticles as a recyclable and reusable heterogeneous acid catalyst in EtOH under reux conditions for 19-32 min. The mechanism of the reaction proceeds with the following steps involving the Michael addition, cyclization and dehydration as presented in Scheme 50. The doping of erbium with TiO 2 NPs increased the efficiency of the resulting catalyst and thus facilitated the reaction in better way as compared with TiO 2 NPs. 81 In 2019, p-toluenesulfonic acid was applied as an efficient and solid acid catalyst for the one-pot, four-component condensation between 3, benzene-1,2-diamines, cyclic 1,3dicarbonyl compounds and isatin or ninhydrin to afford the corresponding spiro[benzo[a]chromeno [2,3-c]phenazine] derivatives 162 in 75-94% yields via a new two-step domino protocol under conventional heating (100 C, 30 min) and microwave irradiation (300 W, 100 C, 7-10 min) under solvent-free conditions. The probable mechanism for the domino synthesis of 162 using p-TSA is given in Scheme 51. Initially with benzene-1,2-diamines obtain benzo[a]phenazin-5-ol 163. Then, the Knoevenagel condensation between the dimedone and cyclic ketone to produce adduct 164, which acts as a Michael acceptor. The enol 163 attacks Knoevenagel adduct 164 in a Michael-type addition to produce intermediate 165 which then makes the inner molecular ring to be formed aer a tautomeric proton shi to generate 162. 82

Synthesis of benzo[a]benzochromeno phenazine
In 2016, an efficient p-toluenesulfonic acid catalyzed synthesis of 11H-benzo[a]benzo [6,7]  mechanism, at rst, 3 tautomerizes to intermediate 24. The primary condensation of 24 with 2a produces 4. With this mechanism, MNPs-thioglycolic acid is an efficient catalyst for forming the olen 171, which is readily prepared in situ from Knoevenagel condensation of carbonyl groups of aldehyde or cyclic ketones 170 with 3. The Michael addition of 4 with olen 171 in the presence of MNPs-thioglycolic acid nally gives intermediate 172, which then makes the inner molecular ring to be formed aer a tautomeric proton shi to produce the target products 168-169. 84 Aer that, Yazdani-Elah-Abadi and his co-workers described the preparation of benzo[a]chromeno[2,3-c]phenazine derivatives 173-175 in 54-89% yields by domino four-component condensation reaction between 3, 2a, aromatic aldehydes, and naphthols or phenol in the presence of a catalytic amount of DABCO (20 mol%) as a reusable base catalyst under microwave irradiation (at 300 W and max. 100 C) in EtOH/H 2 O (1 : 1) within 20-40 min. The probable mechanism is outlined in Scheme 54. On the basis of this mechanism, the primary condensation of 3 with 2a in the presence of DABCO gives 4. Based on this mechanism, DABCO is an efficient catalyst to form the olen 176, which is readily prepared in situ from the Knoevenagel condensation of aromatic aldehyde with naphthols. In the presence of DABCO, 4 converts to its corresponding enolate form 177, to be able to react (Michael addition) easily with 176 and to eventually give rise to the formation of intermediate 178, which then makes the inner molecular ring be formed aer a tautomeric proton shi to produce the desired products 173-175. 85

Synthesis of benzopyridophenazines
In 2017, L-proline has been used as a reusable and bifunctional organocatalyst for the one-pot, two-step, ve-component synthesis of 1,4-dihydrobenzo[a]pyrido [2,3-c]phenazines 179 in 76-87% yields by the condensation reaction of 3, aromatic 1,2-diamines, aldehydes, ammonium acetate and ethyl acetoacetate under conventional heating in solvent-free conditions at 80 C for 20-30 min. The probable mechanism is outlined in Scheme 55. On the basis of this mechanism, the primary condensation of 3 with benzene-1,2-diamines in the presence of L-proline gives benzo[a]phenazin-5-ol 180. On this mechanism, L-proline is an efficient catalyst to form the olen 181, which readily prepares in situ from Knoevenagel condensation of aromatic aldehyde with 180. On the other hand, NH 3  dehydration reactions between 188 and 6-amino-1,3dimethyluracil. 87 Next, an environmentally benign procedure for the synthesis of heteroaryl-substituted dihydrobenzo which then makes the inner molecular ring to be formed aer a tautomeric proton shi to produce the corresponding product 192. 89

Conclusions
Phenazine and its derivatives such as benzophenazins are a large group of natural and synthesized N-containing heterocycles. Benzophenazins have attracted interest because they exhibit a wide range of biological activities. In this article review, we focused on the important methods for synthesis of lawsone-based benzo[a]phenazin-5-ol derivatives and reported the different important reactions of them in synthesis of ve and six membered fused heterocycles and the other derivatives. Moreover, the present work contributes the different classical methods with green approach, homogeneous and heterogeneous-catalyzed reactions, microwave irradiation and ultrasound-mediated reactions for the synthesis of benzophenazine derivatives. Thus, this review article will help not only to the synthetic chemists but also to the medicinal and pharmaceutical chemists to update information on recent developments in this eld.

Conflicts of interest
There are no conicts to declare.